The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical "hot" versus "cold" tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field.

Keywords: T cell; fibroblast; macrophage; myeloid-derived suppressor cell; neutrophil; pancreatic ductal adenocarcinoma; tumor microenvironment.

Figure 1

The tumor immune microenvironment in pancreatic ductal adenocarcinoma involves complex, opposing interaction networks. Presence of both “hot” (red circle) and “cold” (blue circle) microenvironments defies the classical paradigm in which these states are mutually exclusive. Instead, processes characteristic of each state are found within the same tumor. IL-1β, interleukin-1β; CXCL1, C-X-C motif chemokine ligand 1; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; T_FH, T follicular helper cell; IL-21, interleukin-21; cDC, conventional dendritic cell; CXCL13, C-X-C motif chemokine ligand 13; Treg, Regulatory T cell; IL-10, interleukin-10; TGF-β, transforming growth factor-β. Created with BioRender.

Figure 2

Immunotherapeutic approaches to the treatment of PDAC that leverage the tumor immune microenvironment. APC, antigen presenting cell; CAR, chimeric antigen receptor; CTL, cytotoxic T cell; LAG-3, lymphocyte-activation gene-3; PD-1, programmed death receptor-1; PD-L1, programmed death-ligand 1; T_ex, exhausted T cell. Adapted from [39]. Created with BioRender.